SUMMARY Despite decades of HIV-1 vaccine research, there are no examples of immunogens or candidate vaccines that consistently elicit potent broadly neutralizing antibodies (bNAbs). Most examples of bNAbs come from natural HIV-1 infection of humans, but even then, they develop only after several years of infection and in only a subset of individuals. Nonetheless, the finding that humans have the potential to make potent bNAbs has spurred intensive research to identify the target epitopes of these antibodies and their developmental pathways from unmutated germline B cell receptor (BCR) to mature bNAb. Recently, research has focused on the coevolutionary pathways of bNAbs and HIV-1 Env sequences that elicit them in hopes of inferring particular Env sequences that can be developed into immunogens that engage and stimulate germline and intermediate ancestor BCRs. This strategy has been championed by investigators pursuing both ?B cell lineage design? and ?reverse vaccinology? approaches to vaccine development. We propose that a major roadblock to rational HIV- 1 vaccine design is the lack of an animal model where the induction of bNAbs can be achieved in a consistent and reproducible manner such that the molecular events responsible for bNAb elicitation can be deciphered and used to guide iterative HIV-1 vaccine design. This HIVRAD application proposes a novel hypothesis and an integrated research plan ? supported by promising new discoveries in SHIV biology, virus-Ab coevolution, and B lineage vaccine design ? to overcome this critical roadblock. We hypothesize that: (i) primary HIV-1 Env glycoproteins, if presented in their native conformation as persistently replicating SHIVs to outbred, genetically diverse rhesus macaques (RMs), will lead to consistent patterns of virus-Ab coevolution that recapitulate those patterns observed in humans infected by HIV-1 strains bearing homologous Envs; (ii) SHIVs containing primary HIV-1 Envs that in humans elicited bNabs, will bind orthologous germline and intermediate ancestor BCRs in RMs, and lead to the development of autologous and heterologous tier 2 neutralizing antibodies; and (iii) by identifying RM germline and intermediate ancestor BCRs that evolve to achieve neutralization breadth, together with their cognate SHIV Env immunogens (?immunotypes?), we will have in hand for the first time a reproducible experimental system in which to iteratively design, test and guide the development of novel vaccine candidates based on both B lineage design and reverse vaccinology platforms. To test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env Evolution and Neutralizing Antibody Elicitation in SHIV Infected Rhesus Macaques and in Humans Infected by HIV-1 Strains bearing Homologous Envs (Shaw); Project 2 - Population Dynamics of Neutralizing B-Cell Responses in SHIV- infected Macaques (Kelsoe); Project 3 - Immunogen Design of HIV Sequential Envelopes Derived from SHIV- infected Macaques (Haynes). These projects will be enabled by Core A - Administrative (Shaw); Core B - Viral and Antibody Gene Sequencing (Hahn); and Core C - Bioinformatics and Statistics (Korber).